This invention relates to a novel composition of matter which possesses potent antidepressant activity as a serotonin uptake inhibitor while avoiding the usual detrimental factors, unwanted effects and adverse toxic or psychological effects associated with such agents. Also disclosed are methods of using said composition to treat depression while avoiding the usual detrimental factors, unwanted effects, and side effects associated with such agents.
The active compound of this composition and method is an optical isomer of the compound fluoxetine which is described in U.S. Pat. Nos. 4,018,895 and 4,194,009 to Molloy, et al. Chemically this isomer is (+)N-methyl-3-phenyl-3-[(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-oxy]-p ropylamine, herein after referred to as S(+) fluoxetine.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy. However, its L-thalidomide counterpart was discovered to be a potent teratogen.
Fluoxetine (Prozac.RTM.), which is the subject of the present invention, is available only as a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers.
The racemic mixture of fluoxetine, in addition to its use as an antidepressant, has been shown to have a wide spectrum of action which includes:
Treatment of diabetes (EPA 88303930.7) PA1 Assisting in weight loss (appetite suppression) (U.S. Pat. No. 4,895,845) PA1 Treatment of alcohol abuse (U.S. Pat. No. 4,777,173) PA1 Analgesia - control of pain (U.S. Pat. Nos. 4,698,342 and 4,594,358) PA1 Treatment of atherosclerosis (U.S. Pat. No. 4,444,778) PA1 Improvement of memory (U.S. Pat. No. 4,647,591) PA1 Treatment of anxiety (U.S. Pat. No. 4,590,213) PA1 Treatment of hypertension (U.S. Pat. No. 4,329,356)
Whereas the foregoing Molloy et al. patents, in addition to the above discussed European patent application and U.S. patents, recognize compounds such as fluoxetine have optically active forms, no example of an optically active form is given. Furthermore, prior art studies with the enantiomers of fluoxetine have generally concluded the fluoxetine enantiomers are equipotent and that there is no advantage in the use of the pure S-enantiomer. See, Robertson et al., J. Med. Chem., 31: pg. 1412-1417 (1988). However, it has now been discovered that there are indeed unforeseen advantages in the use of the pure S-enantiomer of fluoxetine.
Fluoxetine is used in the treatment of depression, which along with mania falls under the heading of affective disorders. Mania and depression are characterized by changes in mood as the primary symptom. Either of these two extremes of mood may be accompanied by psychosis with disordered thought and delusional perceptions. Psychosis may have, as a secondary symptom, a change in mood, and it is this overlap with depression that causes much confusion in diagnosis. Severe mood changes without psychosis frequently occur in depression and are often accompanied by anxiety. Depression is characterized by feelings of intense sadness or pessimistic worry, agitation, self-deprecation, physical changes (including insomnia, anorexia, and loss of drive, enthusiasm, and libido), and mental slowing. Among the more common treatments for depression are the administration of a tricyclic antidepressant agent.
Fluoxetine is not in the class of drugs known as tricyclic antidepressants. Its antidepressant action is presumed to be based on its highly specific inhibition of serotonin uptake in serotoninergic neurons in the brain. It is also chemically unrelated to tetracyclic or other available antidepressant agents.
Fluoxetine has certain advantages over other antidepressant drugs. Antagonism of muscarinic, histaminergic and .alpha..sub.1 adrenergic receptors has been hypothesized to be associated with various anticholinergic and cardiovascular effects of classical tricyclic antidepressant drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently than do these tricyclic antidepressants. Thus, fluoxetine gives less anticholinergic side effects such as blurred vision, dry mouth, constipation and urinary retention. There is also less lowering of blood pressure, tachycardia and arrhythmias.
While fluoxetine has certain advantages, it also has disadvantages. Among these disadvantages are side effects other than the ones described above. The most frequent reported side effects associated with fluoxetine are headaches, nervousness, anxiety and insomnia. These are reported by 10% to 15% of patients treated with fluoxetine. These symptoms led to drug discontinuation in 5% of the patients treated with the drug. It is also known that in some patients use of fluoxetine is associated with severe anxiety leading to intense violent suicidal thoughts. Teicher et al., Am. J. Psychiatry, 147:2 pg. 207-210 (1990). In other patients manic behavior follows treatment with fluoxetine. Other side effects associated with fluoxetine include nausea, diarrhea and drowsiness.
Another disadvantage of fluoxetine is its long half-life and the concominant delay in onset of action. The half-life of fluoxetine is approximately 2 to 3 days. Steady state plasma concentrations are achieved only after continuous dosing for weeks.
A further disadvantage of fluoxetine is that it has a low response rate. Overall, 44% of the patients being treated with fluoxetine showed antidepressant effect. In patients who had not previously responded to other anti-depressant therapy the response to fluoxetine was 43%. In addition, in patients with no previous treatment with anti-depressants, or with a history of good response to previous treatment, response to fluoxetine was 56%. (Scrip's New Product Review, pages 13-14, 1986).
Another disadvantage of fluoxetine is that in addition to its use as an antidepressant it has other activity such as severe appetite suppression, drowsiness, analgesia and hypotension. These other activities may be unwanted effects when treating a patient suffering from depression.
It is therefore desirable to find a compound with the advantages of fluoxetine which would not have the above described disadvantages.